The discovery that vitamin D3 is a precursor to a functionally active hormone, 1,25-dihydroxyvitamin D3, occurred more than 30 years ago. Subsequent studies have led to our current understanding that vitamin D3 is made from 7-dehydrocholesterol in the skin after exposure to ultraviolet light, modified by vitamin D3-25-hydroxylase in the liver, and then by 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1) in the kidney to form the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol, commercially available under the brand name CALCIJEX from Abbott Laboratories, Abbott Park, Ill.). Calcitriol functions by binding to the Vitamin D receptor (hereinafter abbreviated as or used interchangeably with “VDR”), a nuclear receptor. The binding of calcitriol to the VDR activates the receptor to recruit cofactors to form a complex that binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. The vitamin D signaling pathway is summarized in FIG. 1.
During the past three decades, a majority of the studies in the VDR field have focused on elucidating calcitriol's biochemical role, e.g., in mineral homeostasis, which covers regulation of parathyroid hormone, intestinal calcium and phosphate absorption and bone metabolism. As shown in FIG. 2, 1α-hydroxylase (CYP27B1) in the kidney is responsible for production of the active metabolite 1α,25-dihydroxy vitamin D3 (calcitriol) which subsequently binds to the VDR and ultimately exerts its physiological effects including modulation of intestinal calcium transport and calcium mobilization in the bone, regulation of parathyroid hormone (PTH) synthesis, and downregulation of CYP27B1 through a feedback mechanism. In turn, PTH stimulates CYP27B1, increases calcium resorption, and decreases phosphate resorption in the kidney. Through the coordinated functions of PTH and calcitriol, the homeostasis of calcium and phosphorous is maintained. Calcitriol is oxidized by CYP24 (24-hydroxylase) to metabolites that are excreted. VDR is found in more than 30 tissues and may have other effects beyond its function in controlling PTH and mineral homeostasis.
As a result of those studies, many new analogs of calcitriol have been developed, some having reduced hypercalcemic effect, and several analogs such as paricalcitol (commercially available under the brand name ZEMPLAR, from Abbott Laboratories, Abbott Park, Ill.) and doxercalciferol (commercially available under the brand name HECTOROL, from Genzyme, Cambridge, Mass.) are currently on the market for the treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). In addition, a few VDR modulators are marketed for the treatment of psoriasis and osteoporosis.
In addition, since VDR is widely distributed in organs and tissues throughout the body, it is likely involved with numerous disease states. Results from numerous preclinical studies suggest that VDR modulators may be beneficial for treating various diseases including cardiovascular diseases (CVD), immune disorders, oncology-related thrombosis, etc.
In particular, several lines of evidence support the idea that VDR plays an important role in the regulation of cardiovascular physiology, the immune system and other biophysiological systems in humans. However, preclinical data have suggested that at least some Vitamin D Receptor activators (hereinafter abbreviated as or used interchangeably with “VDRAs”) and/or vitamin D analogs, especially at higher doses, can cause hypercalcemia, which is linked to vascular calcification, myocardial infarction, heart failure, cardiomyopathy and cerebrovascular accidents. Therefore, the medical community does not endorse use of these compounds as a therapy for cardiovascular disease, but rather recommends only limited use.
Similarly, although some VDRAs and/or vitamin D analogs are currently used to treat psoriasis, an immune disorder, their usage is limited due to the concern about hypercalcemic side effects.
Recent data compares survival of patients with chronic renal disease undergoing hemodialysis and treated with either calcitriol or paricalcitol (Teng, M. et al. N. Engl. J. Med., 2003, 349, 446-456.). There was a significant survival benefit to those patients on paricalcitol compared to those on calcitriol. Although calcium and phosphorous levels had increased to a lesser degree in paricalcitol treated patients, the study does not differentiate whether or not the enhanced survival benefit of paricalcitol was due to improvement in mineral imbalance or effect of a specific vitamin D therapy. Additionally, the survival rate did not associate with vitamin D receptor activator dose and was independent of baseline serum calcium, phosphorous or parathyroid hormone levels, suggesting that the cause of lower morbidity may not be closely tied to these disease marker levels. In fact, the actual mechanism of the benefit has not been determined. However, since cardiovascular disease is the cause of death in the majority of dialysis patients, patient survival may be enhanced by paricalcitol's effects on the cardiovascular system.
Other studies (Salusky, I. B.; Goodman, W. G. Nephrology, Dialysis and Transplantation, 2002, 17, 336-339.) show that vitamin D receptor activator therapy may actually worsen survival rate in patients with chronic kidney disease as a result of side effects such as vascular calcification. This has led the medical community to limit usage of vitamin D receptor activator therapy.
An alternative therapy to vitamin D receptor activator therapy is provided by calcimimetics such as Cinacalcet (Sensipar®, Amgen). By contrast, Cinacalcet lowers parathyroid hormone levels by increasing the sensitivity of the calcium-sensing receptor of the parathyroid gland. There are, however, limitations to this therapeutic approach. Both hypersensitivity and severe hypocalcemia are noted contraindications. Dose titration is required to establish the optimal therapy. Several clinicians have suggested co-administration with a VDRA as an approach to treating secondary hyperparathyroidism.
Administration of pharmacological vitamin D receptor activator therapy conventionally involves titrating the dose to an effect, either correcting parathyroid hormone and/or serum calcium levels. Overdosing is monitored to prevent toxicities. It may therefore be advantageous to develop vitamin D receptor activators that have beneficial effects such as reduction of parathyroid hormone levels in chronic renal disease over a wide dosage range while having limited effect on increasing serum calcium levels, essentially increasing the therapeutic window. There also appears to be a survival benefit perhaps associated with improved cardiovascular health. Certainly, preclinical studies have shown a desirable improvement as indicated by cardiovascular markers. Improvements in these aspects of vitamin D receptor activator therapy present the opportunity to expand use of vitamin D receptor activator therapy.
Vitamin D derivatives are complex molecules and their synthesis can be challenging. For example, the synthesis of compounds with the unnatural 20S stereochemistry requires both a method for the epimerization of the C20 center (as designated with the vitamin D numbering system and shown on Formula (I)), as well as a method for the separation of the two resulting isomers, which is typically chromatography. Thus, mild conditions for the epimerization, and a chemical method for distinguishing between the isomers would assist the synthesis of these compounds.
Likewise, the reported synthesis of A-rings containing the 2-methylene moiety (see above regarding numbering) requires only six steps, but the overall yield is poor, and there are no crystalline intermediates to assist in purification.
In addition, the final coupling of the A-ring moiety to the C/D ring typically proceeds in poor yield; a better coupling protocol would make Vitamin D derivatives more available.